Synthesis of Macrocyclic Peptide-Diterpenoid Conjugates by a Sequential Arylation/Peptide Coupling/Click Macrocyclization Procedure

Abstract

An approach relying on a sequential selective arylation of isopimaric acid/peptide coupling/CuAAC-based macrocyclization procedure of alkynyl peptides to azidoditerpenoid, was developed for the preparation of novel triazole-linked peptide -tricyclic diterpenoid conjugates. The process has comprised the synthesis of azidoditerpenoid bearing the azido group at the side chain by the cross-coupling reaction of isopimaric acid with 1-azido-2-iodobenzene as well as the preparation of a small library of dipeptides featuring varied amino acid sequence (Gly-Gly, Gly-Val, Val-Gly and Val-Val). This approach has shown great chemical efficiency and gave macrocyclic compounds in good yields. It was shown that the yield of macrocyclization products depends on the substituent in the dipeptide fragment. The cytotoxicity of the synthesized compounds was evaluated using the conventional MTT assays. It has been found that the introduction of a dipeptide fragment into the structure of isopimaric acid and macrocyclization have a significant effect on toxicity towards human cancer cells